Friday, 25 November 2011

There has been a lot of interest over the past week in the
Burzynski Clinic, a US
organisation that offers unorthodox treatment to those with cancer. To get up
to speed on the backstory see this blogpost by Josephine
Jones.

As someone who spends more of my time than I’d like
grappling with research ethics committees, there was one aspect of this story
that surprised me. According
to this blogpost, the clinic is not allowed to offer medical treatment, but
is allowed to recruit patients to take part in clinical trials. But this is
expensive for participants. The Observer piece that started all the uproar this
week described how a family needed to raise £200,000 so that their very sick
little girl could undergo Burzynski’s treatment.

I had assumed that this trial hadn’t undergone ethical
scrutiny, because I could not see how any committee could agree that it was
ethical to charge someone enormous sums of money to take part in a research
project in which there was no guarantee of benefit. I suspect that many people
would pay up if they felt they’d exhausted all other options. But this doesn’t
mean it’s right.

I was surprised, then, to discover that the Burzynski trial had undergone review by an Institutional
Review Board (IRB - the US
term for an ethics committee). A
letter describing the FDA’s review of the relevant IRB is available on the
web. It concludes that “the IRB did not adhere to the applicable statutory
requirements and FDA regulations governing the protection of human
subjects.” There’s a detailed exposition
of the failings of the Burzynski Institute IRB, but no mention of fees charged to
patients. So I followed a few more links and came to a US government
site that described regulatory guidelines for ethics committees, which had a
specific section on Charging
for Investigational Products. It seems the practice of passing on research
costs to research participants is allowed in the US system.

There has been considerable debate in academic circles about
the opposite situation, where participants are paid to take part in a study. I know of cases where such payments
have been prohibited by an ethics committee on the grounds that they provide
‘inducement’, which is generally regarded as a Bad Thing, though there are convincing
counterarguments.
But I am having difficulty in tracking down any literature at all on the ethics
of requiring participants to pay a fee to take part in research. Presumably
this is a much rarer circumstance than cases where participants are paid,
because in general people need persuading to take part in research. The only
people who are likely to pay large sums to be a research participant are those
who are in a vulnerable state, feeling they have nothing to lose. But these are
the very people who need protection by ethics committees because it’s all too
easy for unscrupulous operators to exploit their desperation. Anyone who
doesn’t have approval to charge for a medical treatment could just redescribe
their activities as a clinical trial and bypass regulatory controls. Surely
this cannot be right.

Saturday, 19 November 2011

I’m always fascinated by the profiles of people who follow
me on Twitter. One of the things I love about Twitter is its ability to link me
up with people who I’d never otherwise encounter. It’s great when I find
someone from the other side of the world who’s interested in the same things as
me. There are, of course, also those who just want to promote their product,
and others, like Faringdon Motor Parts and Moaning Myrtle (@toiletmoans) whose
interests in my tweets are, frankly, puzzling. But the ones that intrigue me
most are the ones with profiles that create an immediate negative impression -
or to put it more bluntly, make me just think "Pillock!" (If you need to look
that up, you’re not from Essex).

Now language is one of my things - I work on language
disorders, and over the years I’ve learned a bit about sociolinguistics - the
influence of culture on language use. And that made me realise there were at
least two hypotheses that could explain the occasional occurrence of offputting
profiles. The first was that I am being followed by genuine pillocks. But the
other was that there are cultural differences in what is regarded as an
acceptable way of presenting yourself to the world. Maybe a turn of phrase that
makes me think "pillock" would make someone else think "cool". And perhaps this
is culturally determined.

So what, to my British ear, sets off the pillock detector?
The major factor was self-aggrandisement. For instance, someone who describes
themselves as "a top intellectual", "highly successful", "award-winning", or "inspirational".

But could this just be a US/UK difference? The British have
a total horror of appearing boastful: the basic attitude is that if you are
clever/witty/beautiful you should not need to tell people - it should be
obvious. Someone who tells you how great they are is transgressing cultural
norms. Either they really are great, in which case they are up themselves, as
we say in Ilford, or they aren’t, in which case they are a dickhead. When
I see a profile that says that someone is "interested in everything, knows
nothing", "a lazy pedant", or "procrastinaor extraordinaire", I think of them
as a decent sort, and I can be pretty sure they are a Brit. But can
this go too far? Many Brits are so anxious to avoid being seen as immodest that
they present themselves with a degree of self-deprecation that can be confused
by outsiders with false modesty at best, or neurotic depression at worst.

A secondary factor that sets off my negative reactions is
syrupy sentiment, as evidenced in phrases such as: "empowering others", "Living my dream", or "I want to share my love". This kind of thing is
generally disliked by Brits. I suspect there are two reasons for this. First,
in the UK,
displays of emotion are usually muted, except in major life-threatening circumstances: so much so that when someone is
unabashedly emotional they are treated with suspicion and thought to be
insincere. And second, Polyannaish enthusiasm is just uncool. The appropriate
take on life’s existential problems is an ironic one.

I was pleased to find my informal impressions backed by by
social anthropologist Kate Fox, in her informative and witty book "Watching the
English" (Hodder & Stoughton,
2004). Humour, she states, is our "default mode", and most English
conversations will involve "banter, teasing, irony, understatement, humorous
self-deprecation, mockery or just silliness." (p 61). She goes on to describe
the Importance of Not Being Earnest rule: "Seriousness is acceptable, solemnity
is prohibited. Sincerity is allowed, earnestness is strictly forbidden.
Pomposity and self-importance are outlawed." (p. 62). Fox doesn’t explicitly
analyse American discourse in the book, but it is revealing that she states: "the kind of hand-on-heart, gushing earnestness and pompous Bible-thumping solemnity
favoured by almost all American politicians would never win a single vote in
this country - we watch these speeches on our news programmes with a kind of
smugly detached amusement." (p 62).

Anthropologists and linguists have analysed trends such as
these in spoken discourse, but I
wondered whether they could be revealed in the attenuated context of a Twitter
profile. So in an idle moment (well, actually when I was supposed to be doing
something else I didn’t want to do) I thought I’d try an informal analysis of
my Twitter followers to see if these impressions would be borne out by the
data. This is easier said than done, as I could find no simple way to download
a list of followers, and so I had to be crafty about using "SaveAs" and "Search
and Replace" to actually get a list I could paste into Excel, and when I did
that, my triumph was short-lived: I found it’d not saved Location information.
At this point, my enthusiasm for the project started to wane - and the task I
was supposed to be doing was looking ever more attractive. But, having started,
I decided to press on and manually enter location for the first 500 followers.
(Fortunately I was able to listen to an episode of the News Quiz while doing
this. I started to like all those eggs with no Location recorded). I then hid that column so it would not bias me, and coded the profiles
for three features: (a) Gender (male/female/corporate/impossible to tell); (b)
Self-promotion: my totally subjective rating of whether the profile triggered
the pillock-detector; (c) Syrupy: another subjective judgement of whether the
profile contained overly sentimental language. I had intended also to code
mentions of cats - I was convinced that there was a British tendency to mention
cats in one’s profile, but there were far too few to make analysis feasible. I
was a victim of confirmation
bias. So were my other intuitions correct? Well, yes and no.

For the analysis I just focused on followers from the US and UK. The first thing to emerge from
the analysis was that pillocks were rare in both US and UK - rarer than
I would have anticipated. I realised that, like mentions of cats, it’s
something I had overestimated, probably because it provoked a reaction in me
when it occurred. But, I was pleased to see that nonetheless my instincts were
correct: there were 7/97 (7.2%) pillocks in the US
sample but only 2/153 (1.3%) in the UK . The sample size is really not
adequate, and if I were going to seriously devote myself to sociolinguistics
I’d plough on to get a much bigger sample size. But nevertheless, for what it’s
worth, this is a statistically significant difference (chi square = 5.97, p =
.015 if you really want to know). Syrup followed a similar pattern: again it was rare in both samples, but
it was coded for 3/153 of the UK
sample compared with 7/97 of the US. I’d coded gender as I had
thought this might be a confounding factor, but in fact there were no
differences between males and females in either pillocks or syrup. Of course,
all these conclusions apply only to my followers, who are bound to be an
idiosyncratic subset of people.

My conclusion from all this: we need to be more sensitive to
cultural differences in self-expression. Looking over some of the profiles that
I categorised as "pillock" I realise that I’m being grossly unfair to their owners. After all, on a Twitter profile, the only information that people have about
you comes from the profile - and your tweets. So it really is preposterous for
me to react negatively against someone telling me they are an "award-winning
author": that should engender my interest and respect. And, because this is a
profile, and not a conversation, if they didn’t tell me, I wouldn’t know. And we really ought to cherish rather than mock those who try to bring a bit of love and kindness into the world. But
somehow….

I hope that Americans reading this will get some insight
into the tortuous mindset of the Brits: if we come across as dysfunctionally
insecure losers it’s not that we really are - it’s that we’d rather you thought
that of us than that we were boastful.

Sunday, 13 November 2011

In November 2003, a
six-month-old boy was admitted to the emergency department of a children’s hospital in Tel Aviv. He had
been vomiting daily for two months, was apathetic, and had not responsed to
anti-emetic drugs. The examining doctor noticed something odd about the child’s
eye movements and referred him on to the neuro-ophthalmology department. A
brain scan failed to detect any tumour. The doctors remembered a case they had
seen 18 months earlier, where a 16-year-old girl had presented with episodic
vomiting and abnormal eye movements due to vitamin B1 deficiency. They injected the child with thiamine and saw
improvement after 36 hours. The vomiting stopped, and over the next six weeks
the eye movements gradually normalised. When followed up 18 months later he was
judged to be completely normal.

This
was not, however, an isolated case. Other babies in Israel were turning up in emergency
departments with similar symptoms. Where thiamine deficiency was promptly
recognised and treated, outcomes were generally good, but two children
died and others were left with seizures and neurological impairment. But
why were they thiamine deficient? All
were being fed the same kosher, non-dairy infant formula, but it contained
thiamine. Or did it? Analysis of samples by the Israeli Ministry of Health
revealed that levels of
thiamine in this product were barely detectable, and there was an immediate
product recall. The manufacturer confirmed that human error had led to thiamine
being omitted when the formula had been altered.

The
cases who had been hospitalised were just the tip of the iceberg. Up to 1000
infants had been fed the formula. Most of these children had shown no signs of neurological
problems. But a
recent study reported in Brain describes a remarkable link between this
early thiamine deprivation and later language development. Fattal and
colleagues studied 59 children who had been fed thiamine-deficient formula for
at least one month before the age of 13
months, but who were regarded as neurologically asymptomatic. Children who had
birth complications or hearing loss were excluded. The authors stress that the
children were selected purely on the basis of their exposure to the deficient
formula, and not according to their language abilities. All were attending
regular schools. A control group of 35
children was selected from the same health centres, matched on age.

Children
were given a range of language tests when they were 5 to 7 years of
age. These included measures of sentence comprehension, sentence production,
sentence repetition and naming. There were dramatic differences between the two
groups of children, with the thiamine-deficient group showing deficits in all
these tasks. The authors argued that the profile of performance was identical
to that seem in children with a diagnosis of specific language impairment
(SLI), with specific problems with certain complex grammatical constructions,
and normal performance on a test of conceptual understanding that did not
involve any language.

Figure 1 An example of a picture pair used
in the comprehension task.

The child is asked to point to the picture that
matches a sentence,

such as ‘Tar’e li et ha-yalda she-ha-isha
mecayeret’

(Show me the girl that the woman draws).
From Fattal et al, 2011.

I
have some methodological quibbles with the paper. The authors excluded three
control children who did poorly on the syntactic tests because they were
outliers - this seems wrong-headed if the aim is to see whether syntactic
problems are more common in children with thiamine-deficiency than in those
without. The non-language conceptual
tests were too easy, with both groups scoring above 95% correct. To convince me
that the children had normal abilities they would need to demonstrate no
difference between groups on a sensitive test of nonverbal IQ. My own
experience of testing children’s grammatical abilities in English is that
ability to do tests such as that shown in Figure 1 can be influenced by
attention and memory as well as syntactic ability, and so I think we need to
rule out other explanations before accepting the linguistic account offered by
the authors. I’d also have liked a bit more information about how the control
children were recruited, to be certain they were not a ‘supernormal’ group - often
a problem with volunteer samples, and something that could have been addressed
if a standarized IQ test had been used. But overall, the effects demonstrated
by these authors are important, given that there are so few environmental factors known to selectively affect language skills. These results raise a number of questions about children’s
language impairments.

The
first question that struck me was whether thiamine deficiency might be
implicated in other cases outside this rare instance. I have no expertise in
this area, but this paper prompted me to seek out other reports. I learned that
thiamine deficiency, also known as
infantile beriberi, is extremely rare in the developed world, and when it
does occur it is usually because an infant is breastfeeding from a mother who
is thiamine deficient. It is therefore important to stress that thiamine deficiency is highly unlikely to
be implicated in cases of specific language impairment in Western societies.
However, a
recent paper reported that it is relatively common in Vientiane, Laos, where there are traditional
taboos against eating certain foods in the period after giving birth. The researchers
suggested that obvious cases with neurological impairments may be the extreme
manifestation of a phenomenon that is widespread in milder form. If so, then
the Israeli paper suggests that the problem may be even more serious than originally suggested, because there could be longer-term adverse effects on language
development in those who are symptom-free in infancy.

The
second question concerns the variation in outcomes of thiamine-deficient
infants. Why, when several hundred children had been fed the deficient formula, were only some of them severely affected? An obvious possibility is the extent to which infants were fed
foods other than the deficient formula. But there may also be genetic
differences between children in how efficiently they process thiamine.

This
brings us to the third question: could this observed link between thiamine
deficiency and language impairment have relevance for genetic studies of language difficulties? Twin
and family studies have indicated that specific language impairment is
strongly influenced by genes. However, one seldom finds genes that have a major
all-or-none effect. Rather, there are genetic risk variants that have a fairly
modest and probabilistic impact on language ability.

Robinson Crusoe Island

A
recent study by Villanueva
et al illustrates this point. They analysed genetic variation in an
isolated population on Robinson Crusoe
Island, the only inhabited island in the Juan
Fernandez Archipelago, 677 km to the west of Chile. At the time of the study
there were 633 inhabitants, most of whom were descended from a small number of
founder indviduals. This population is of particular interest to geneticists as
there is an unusually high rate of specific language impairment. A genome-wide analysis failed to identify any
single major gene that distinguished affected from unaffected individuals.
However, there was a small region of chromosome 7 where there genetic structure
was statistically different between affected and unaffected cases, and which
contained genetic variants that had previously been found linked to language
impairments in other samples. One of these, TPK1 is involved in the catalysis
of the conversion of thiamine to thiamine pyrophosphate. It must be stressed
that the genetic association between a thiamine-related genetic variant
and language impairment isprobabilistic and weak, and far more research
will be needed to establish whether it is generalises beyond the rare
population studied by Villanueva and colleagues. But this observation points
the way to a potential mechanism by which a genetic variant could influence
language development.

To sum up: the
importance of the study by Fattal and colleagues is two-fold. First, it
emphasises the extent to which there can be adverse longer-term consequences of
thiamine deficiency in children who may not have obvious symptoms, an
observation which may assume importance in cultures where there is inadequate
nutrition in breast-feeding mothers. Second, it highlights a role of thiamine
in early neurodevelopment, which may prove an
important clue to neuroscientists and geneticists investigating risks for language impairment.

References

Fattal I, Friedmann N, & Fattal-Valevski A (2011). The crucial role of thiamine in the development of syntax and lexical retrieval: a study of infantile thiamine deficiency. Brain : a journal of neurology, 134 (Pt 6), 1720-39 PMID: 21558277